Injectable and Strong Nano-Apatite/Stem Cell Scaffolds for Bone Regeneration

项目总结/摘要 在美国，每年有700万人骨折，肌肉骨骼疾病的费用为215美元。 亿元/年。这些数字随着人口老龄化而增加。磷酸钙骨水泥（CPC）可以 成型并原位固化以形成羟基磷灰石，具有骨传导性，并且可以被再吸收并被新的 骨头然而，CPC的低强度限制了其在非应力位置的使用。在最初的五年里， 格兰特，开发了一组新的强和大孔CPC。具有长大孔的支架， 生成组织向内生长和定制强度历史。目前，用于干细胞的预制载体 递送难以将细胞接种到支架深处，并且不能以微创方式注射。 程序.目前的可注射载体很弱，不能用于广泛的承重修复。 因此，我们未来五年的目标是开发可注射的、强的、坚韧的和大孔的纳米- 用于牙科、颅面和整形外科应用的具有干细胞和生长因子递送的磷灰石支架。 在目标1中，将开发一类新的可注射的、强的、坚韧的和大孔的CPC。的假设 是：（i）CPC组合物可以定制，以提高可注射性和强度;（ii）优化增强 和大孔隙率将产生具有高应变的CPC，以适应组织内的微动;（iii） 仿生纳米磷灰石支架将增强间充质干细胞的定植和分化 骨髓间充质干细胞（MSC）来源于大鼠骨髓。目标2将研究生长因子的输送并检验这些假设： (i)可配制快速凝固、坚固和大孔CPC-生长因子载体;（ii）生长因子 从CPC的释放与孔体积分数成比例;（iii）控制多个生长的顺序释放 可以实现优化干细胞功能的因素。目标3将提供干细胞并测试这些假设： (i)干细胞可以封装在水凝胶中并掺入CPC中，而不会降低细胞活力， （ii）水凝胶珠可以溶解以释放细胞并伴随产生互连的细胞分化; （iii）干细胞和生长因子可以在同一载体中共同递送，以增强细胞增殖; 功能目的4将评估动物模型中的骨再生并测试这些假设：（i）大孔 CPC递送干细胞和成骨和血管生成生长因子将被完全吸收， 在大鼠的整个临界尺寸的颅骨缺损中被新骨取代;（ii）可注射的，坚固的， 大孔CPC具有比传统CPC高得多的再吸收和新骨形成速率;（iii） 优化支架成分、大孔隙率和多种生长因子将极大地增强骨 通过干细胞形成。这种新一代可注射、坚固且大孔的纳米磷灰石支架 与干细胞和生长因子的递送预期具有牙科、颅面和整形外科应用， 大大增强了骨再生，以改善数百万人的健康和生活质量。

Project Summary/Abstract Seven million people suffer bone fractures annually in the U.S. Musculoskeletal conditions cost $215 billion/year. These numbers are increasing as the population ages. Calcium phosphate cement (CPC) can be molded and set in-situ to form hydroxyapatite, is osteoconductive, and can be resorbed and replaced by new bone. However, the low strength of CPC limits its use to non-stress locations. In the original five years of this grant, a new group of strong and macroporous CPCs were developed. Scaffolds with long macropores for tissue ingrowth and tailored strength history were generated. Currently, pre-fabricated carriers for stem cell delivery have difficulty in seeding cells deep into the scaffold, and cannot be injected in minimally-invasive procedures. Current injectable carriers are weak and cannot be used in a wide range of load-bearing repairs. Therefore, our objective for the next five years is to develop injectable, strong, tough, and macroporous nano- apatite scaffolds with stem cell and growth factor delivery for dental, craniofacial and orthopedic applications. In Aim 1, a new class of injectable, strong, tough and macroporous CPCs will be developed. The hypotheses are: (i) CPC composition can be tailored to improve injectability and strength; (ii) Optimizing the reinforcement and macroporosity will yield CPC with high-strain to accommodate for micro-motions within the tissues; (iii) The biomimetic nano-apatite scaffolds will enhance the colonization and differentiation of mesenchymal stem cells (MSCs) derived from rat bone marrow. Aim 2 will investigate growth factor delivery and test these hypotheses: (i) Fast-setting, strong and macroporous CPC-growth factor carrier can be formulated; (ii) Growth factor release from CPC is proportional to pore volume fraction; (iii) Controlled sequential release of multiple growth factors can be achieved to optimize stem cell function. Aim 3 will deliver stem cells and test these hypotheses: (i) Stem cells can be encapsulated in hydrogel and incorporated into CPC without decreasing cell viability and differentiation; (ii) Hydrogel beads can dissolve to release the cells and concomitantly create interconnected macropores in CPC; (iii) Stem cells and growth factors can be co-delivered in the same carrier to enhance cell function. Aim 4 will evaluate bone regeneration in animal models and test these hypotheses: (i) Macroporous CPC delivering stem cells and osteogenic and angiogenic growth factors will be completely resorbed and replaced by new bone across the entire critical-sized cranial defect in rats; (ii) The injectable, strong and macroporous CPCs have much higher resorption and new bone formation rates than traditional CPC; (iii) Optimizing the scaffold composition, macroporosity, and multiple growth factors will greatly enhance bone formation via stem cells. This new generation of injectable, strong and macroporous nano-apatite scaffolds with stem cell and growth factor delivery are expected to have dental, craniofacial and orthopedic applications, with greatly enhanced bone regeneration to improve the health and quality of life for millions of people.